DESCRIPTION: (Applicant's Abstract) This research proposal examines the hypothesis that prenatal cocaine exposure alters nigrostriatal dopamine transmission in rat offspring. The functional integrity of nigrostriatal dopamine neurons after prenatal cocaine exposure will be assessed by measuring endogenous dopamine release and dopaminergic modulation of acetylcholine release from superfused rat striatal slices. Studies will examine the responsiveness of slices to electrical stimulation and to a variety of pharmacological drugs that affect several aspect of transmitter release including reuptake inhibition, receptor stimulation, and receptor blockade. This approach may reveal discrete effects of prenatal cocaine. Studies outlined in this proposal will examine the role of serotonin on dopamine transmission in rats exposed to cocaine prenatally. Earlier research has demonstrated that serotonin can modulate dopamine release from nigrostriatal afferents and striatal acetylcholine release. Recently it has been shown that prenatal cocaine exposure results in serotoninergic hyperinnervation of the striatum. Thus, dopamine transmission after prenatal cocaine exposure may be regulated by an inhibitory influence of these hyperinnervated terminals. Behavioral consequences of prenatal cocaine will be assessed by measuring stereotypy, a behavior that appears to involve striatal cholinergic neurons, in response to dopaminergic, serotonergic, and cholinergic drugs. The results of these studies should enhance our understanding of the effects of prenatal cocaine on interactions between striatal transmitters at neurochemical and behavioral levels. Moreover, examination of the effects of prenatal cocaine on stereotypy may yield valuable insights into postsynaptic consequences of alterations in dopamine transmission from prenatal cocaine exposure. The final group of experiments was designed to examine reported increases in behavioral sensitivity to cocaine in female rats and specifically whether female offspring are exposed to such increases. Investigating the impact o prenatal cocaine in female subjects should further our understanding of the basis for increased sensitivity to cocaine. By characterizing prenatal cocaine effects in prepubertal juvenile rats vs adult female rats, the contribution of female hormones on nigrostriatal interactions and behavior can be assessed. There are several health-related aspects of the studies cited in this proposal. First, by providing insights into alterations of striatal interactions in response to prenatal cocaine, we may be able to draw some parallels between findings in animals and findings in human babies exposed to cocaine in utero. These infants experience tremors and restlessness that may be indicative of changes in nigrostriatal basal ganglia circuitry. Second, evaluation of serotonergic hyperinnervation on dopamine transmission in prenatally cocaine exposed animals could lead to the development of serotonergic drugs to curb alterations in motor activity observed in human infants exposed to cocaine. Third, the results of the studies cited in this proposal may relate to issues involving propensity of children of cocaine-addicted mothers to abuse cocaine and to sex differences in cocaine sensitivity.